1. Field of the Invention
This invention relates to pharmaceutically active mercaptosulfide derivatized peptides useful as inhibitors of the matrix metalloproteinase (MMP) family of enzymes for use in modulating physiological functions or treating diseases and disease conditions associated with MMP modulation, for example: arthritic diseases, such as osteoarthritis (OA), rheumatoid arthritis (RA), septic arthritis, soft tissue rheumatism, polychondritis and tendonitis; tumor invasion in certain cancers; periodontal diseases; corneal ulceration, e.g., that induced by alkali or other burns, by radiation, by vitamin E or retinoid deficiency; glomerular diseases, such as proteinuria, dytrophobic epidermolysis bullosa; bone resorption diseases, such as osteoporosis, Paget's disease, hyperparathyroidism and cholesteatoma; birth control through preventing ovulation or implantation; angiogenesis relating to tumor growth or to the neovascularization associated with diabetic retinopathy and macular degeneration; coronary thrombosis associated with atherosclerotic plaque rupture; and pulmonary emphysema. In addition to the compounds and their use, the invention also relates to their precursors, to their preparation and to pharmaceutical compositions using the compounds of the invention.
2. Background Information
The MMPs are a family of zinc-containing proteinases believed to be responsible for the metabolic turnover of protein components of the extracellular matrix of humans. At present there are at least eight known human MMP.
Various disease and disease conditions have been linked with the actions or presence of MMP, e.g., elevated levels of certain of these enzymes exists in joints of arthritic humans and animals and therefore have been linked to the degradation of the major components of articular cartilage and basement membranes. It is presently believed that the collective action of the MMP on extracellular matrix macromolecules is responsible for the destruction of connective tissue, however, the precise role of each enzyme in the process is not yet well understood. It has also been reported that certain MMP may be instrumental in mediating certain normal physiological functions that involve the breakdown or development of tissue.
It has been desired to selectively inhibit certain MMP enzymes, specifically those which modulate certain diseases, physiological conditions and disease conditions, in order that such conditions could be controlled.
It has been surprisingly discovered that a family of mercaptosulfide derivatized polypeptides are potent inhibitors of MMP, thereby affording a method of treating MMP-mediated diseases and disease conditions, and controlling MMP-mediated physiological functions.